Spot urine protein to creatinine ratio testing : new techniques for detecting proteinurra in pre-eclampsia.

Abstract

Background: The most commonly employed screening method for proteinuria is a semi- quantitative dipstick urinalysis, but it has been shown to be inaccurate in pregnancy. New developments in the assessment of proteinuria have included the use of urinary albumin measurements. The Clinitek Microalbumin Reagent Strip (Bayer Healthcare LLC, USA) is a semi-quantitative dipstick test. It is used to measure the spot urinary microalbumin to creatinine ratio that is read using the Clinitek 50 portable urine chemistry analyzer. Aims We embarked on a pilot study to validate the Clinitek 50 system by determining the accuracy of spot urinary microalbumin to creatinine ratio dipsticks and conventional visual dipsticks (Makromed) compared to the laboratory urinary microalbumin to creatinine ratio quantification to detect significant proteinuria in normotensive and hypertensive antenatal attendees. The accuracy of spot urinary microalbumin to creatinine ratio dipsticks and conventional visual dipsticks were then compared to a 24 hour urinary protein (gold standard) to detect significant proteinuria in hypertensive disorders of pregnancy. We then determined the role of proteinuria as assessed by the diagnostic accuracy of both the 24 hour urinary protein (gold standard) and the spot urinary microalbumin to creatinine ratio dipstick, in pregnancy outcomes of these participants. Methods This was a prospective study conducted at hospitals serving the Durban Metropolitan region in South Africa. To validate the urinary microalbumin to creatinine ratio dipstick, fifteen normotensive healthy pregnant women and 11 women with new onset hypertension in pregnancy were recruited .Each women had a spot midstream urine, which was assessed for proteinuria using a semi-quantitative visual dipstick (Makromed) and analysed using the semi-quantitative urinary microalbumin to creatinine ratio dipsticks (Clinitek® Microalbumin) read on the Clinitek® 50 urine chemistry analyser. A result of 1 + on visual dipsticks and a spot urinary microalbumin to creatinine ratio UAC of > 300mg/g (33.9mg/mmol) was considered as positive for significant proteinuria. The results were compared to the laboratory quantitative measurement of the urinary microalbumin to creatinine ratio. The study group comprised 163 women presenting with newly diagnosed hypertension during pregnancy after 20 weeks of gestation, being recruited from antenatal clinics. Each participant had a spot urine sample that was tested by trained midwives for proteinuria using a semi-quantitative visual dipstick (Makromed). Participants were admitted to the ward where a spot midstream urine sample was collected and analysed using the semi-quantitative urinary microalbumin to creatinine ratio dipsticks. A 24 hour quantitative urinary protein analysis was completed. The results of the urinary microalbumin to creatinine ratio dipsticks and conventional visual dipsticks were compared to the 24 hour urinary protein (gold standard) to detect significant proteinuria. A urinary microalbumin to creatinine ratio of < 300mg/g (nil and trace on visual urine dipsticks) was considered to be a negative result. A urinary microalbumin to creatinine ratio 300 mg/g (1+ to 4+ on visual urine dipsticks) was considered to be a positive result. Urinary protein 0.3 g/24 hours was considered significant proteinuria. The outcomes of pregnancy in 2 sub-categories viz. those with and without significant proteinuria were compared using the 24 hr urinary protein measurement. A secondary analysis of outcomes of pregnancy was performed by subcategorizing the participants according to the diagnostic accuracy of the urinary microalbumin to creatinine ratio dipsticks. In the 26 patients enrolled in the initial study , the visual dipstick had a sensitivity of 25% ( 95% CI [0.04-0.64] ) and specificity of 89% ( 95% CI [0.64 -0.98]).The urinary microalbumin to creatinine ratio dipsticks had a sensitivity of 88% ( 95% CI [0.47-0.99]), specificity of 89% (95% CI [0.64-0.98]), negative predictive value (NPV) of 94% (95% CI [0.69-1.00]) and positive predictive value (PPV) of 78% (95% CI [0.40-0.96]). In the 163 patients subsequently enrolled the visual dipstick had a sensitivity of 51 % ( 95% CI [0.41-0.61]) and specificity of 91% (95% CI [0.81-0.96]) .The PPV and NPV was 89 %( 95% CI [0.77-0.95]) and 58% (95% CI [0.48-0.67]) respectively. The urinary microalbumin to creatinine ratio dipsticks had a sensitivity of 63% (95% CI [0.52-0.72]) and specificity of 81 % (95% CI [0.70-0.89]). The PPV was 82% (95% CI [0.71-0.90]) and NPV was 62% (95% CI [0.51-0.71]). Our results show that in hypertensive pregnant women, significant proteinuria determined by the quantitative 24 hour urinary protein is associated with delivery at an earlier gestational age, increased induction of labour and lower birthweights compared to the non-proteinuric hypertensives (gestational hypertension). There is also a trend towards an increased maternal morbidity and perinatal mortality. When the groups were classified into pre-eclampsia and gestational hypertension using the diagnostic accuracy of the urinary microalbumin to creatinine ratio dipsticks, there were no differences in the clinical outcomes between the false negatives and true negatives except a trend towards a higher caesarean section rate in the false negatives. Conclusion The urinary microalbumin to creatinine ratio dipstick read on the Clinitek 50 system provides a semi – quantitative result of the urinary microalbumin to creatinine ratio that has good sensitivity and specificity. Furthermore, the urinary microalbumin to creatinine ratio dipstick has a good negative predictive value and a result of < 300mg/g rules out significant proteinuria and avoids unnecessary investigations in pregnancy. Both the visual dipstick (Makromed) and the urinary microalbumin to creatinine ratio dipstick read on the Clinitek 50 system are not accurate when compared to the total 24 hour urinary protein. Differences between the urinary microalbumin to creatinine ratio and 24 hour total urinary protein may be due to the variation in the albumin fraction of the total urinary protein of pre-eclampsia, technical problems with imprecision of the assay technique and clinical causes of false positives and negatives. The improved sensitivity of the automated urinary microalbumin to creatinine ratio dipstick over the visual dipstick suggests it may be a suitable substitute for the visual dipstick in clinical practice Hypertension in pregnancy associated with significant proteinuria is associated with greater adverse maternal and fetal outcome. Outcome of pregnancy is similar when a classification of gestational hypertension is made based either on the 24 hour urinary protein or the urinary microalbumin to creatinine ratio dipstick read on the Clinitek 50 system. The urinary microalbumin to creatinine ratio dipstick is a good screening test to rule out significant proteinuria. It has the potential to improve accuracy of screening for proteinuria and enhancing safety by preventing incorrect diagnosis and unnecessary investigation. Further research is required to determine its full impact and cost effectiveness in the clinical setting.